The Journal of Neurophysiology Vol. 87 No. 3 March 2002, pp. 1271-1279
Copyright ©2002 by the American Physiological Society

Sodium Channel Blocking Actions of the -Opioid Receptor Agonist U50,488 Contribute to Its Visceral Antinociceptive Effects

Department of Pharmacology, College of Medicine, The University of Iowa, Iowa City, Iowa 52242

Su, X., S. K. Joshi, S. Kardos, and G. F. Gebhart. Sodium Channel Blocking Actions of the -Opioid Receptor Agonist U50,488 Contribute to Its Visceral Antinociceptive Effects. J. Neurophysiol. 87: 1271-1279, 2002. The goal of the present study was to determine whether the -opioid receptor agonist (ORA) U50,488 attenuates behavioral and primary afferent nerve responses to noxious colorectal distension (CRD) by sodium channel blockade. We tested the analgesic -ORA (±)-trans U50,488, its enantiomers ()-trans (1S,2S)-U50,488 and non -ORA (+)-trans (1R,2R)-U50,488, and/or its diastereomer ()-cis (1S,2R)-U50,488 for their ability to attenuate visceromotor and pelvic nerve afferent fiber responses to noxious CRD in vivo and voltage-activated sodium current in colon sensory neurons in vitro. In unanesthetized rats, subcutaneous administration of U50,488, (1S,2S)-U50,488, and (1R,2R)-U50,488 attenuated the behavioral visceromotor response to noxious CRD; the rank order of potency was: (1S,2S)-U50,488 > U50,488 (1R,2R)-U50,488. U50,488 and its stereoisomers also inhibited responses of decentralized pelvic nerve afferent fibers to noxious CRD in a dose-dependent manner. Cumulative doses of 16 mg/kg of (1S,2S)-U50,488, (1S,2R)-U50,488, and (1R,2R)-U50,488 reduced responses to a mean 29, 30, and 47% of control, respectively. The mean inhibitory doses of these drugs were not different (range: 6.6-10.8 mg/kg). Sodium channel blockers mexiletine and carbamazepine mimicked the effect of U50,488. In contrast, the -ORAs dynorphin (1-13) and ICI 204,488 were ineffective in attenuating pelvic nerve activity. Perfusion of (1S,2S)-U50,488, (1S,2R)-U50,488, or (1R,2R)-U50,488 on colon sensory neurons in vitro decreased voltage-activated sodium currents. This inhibition by U50,488 and its stereoisomers was not opioid receptor-mediated because it could not be reversed by the opioid receptor antagonist naloxone and was also not a G protein-mediated effect. The results reported here suggest that the visceral antinociceptive effects of U50,488 and its stereoisomers are contributed to by their peripheral sodium channel blocking actions.